Transplantation of the bone marrow microenvironment leads to hematopoieticchimerism without cytoreductive conditioning

Background. It has been hypothesized that regimens to induce transplantatio n tolerance and long-term hematopoietic chimerism require recipient conditi oning with whole body irradiation or a cytoablative regimen to create space within the marrow microenvironment to permit pluripotent stem cell engraft ment. The purpose of this study was to determine if transplantation of an i ntact bone marrow microenvironment in the form of a bone graft would permit stable hematopoietic stem cell engraftment, shape the repertoire of develo ping T cells, and induce donor-specific unresponsiveness in the absence of a conditioning regimen. Methods. Fragments of femur were transplanted under the kidney capsule of r ecipient mice. At defined time points after bone graft transplantation reci pients were assayed for chimerism, bone graft viability, and responses to d onor and third party alloantigens in vitro and in vivo. Results. In the absence of an immunological barrier, bone graft transplanta tion resulted in long-term multi-lineage hematopoietic chimerism in the per ipheral blood. Nude bone graft transplantation into SCID recipients resulte d in development of donor- derived T cells that underwent negative selectio n on bone graft derived I-E+ cells within the thymus. Across a fully alloge neic barrier in immunocompetent recipients treated with combined blockade o f the CD40 and CD28 pathways bone graft transplantation resulted in long te rm donor-specific hyporesponsiveness in vitro and acceptance of donor speci fic skin grafts. Conclusions. Transplantation of bone marrow in the form of a bone graft may facilitate the production of hematopoietic chimerism and lead to long-term donor-specific hyporesponsiveness in the absence of a cytoreductive condit ioning regimen.